Solid dosage formulations of an orexin receptor antagonists

ABSTRACT

The present invention is directed to a pharmaceutical composition comprising the compound suvorexant, or a pharmaceutically acceptable salt thereof, a concentration-enhancing polymer, and optionally a pharmaceutically acceptable surfactant. The concentration-enhancing polymer is a polymer that forms an amorphous dispersion with suvorexant, that is insoluble or almost completely insoluble in water by (a) dissolving the suvorexant or (b) interacting with the suvorexant in such a way that the suvorexant does not form crystals or crystalline domains in the polymer. A concentration-enhancing polymer is water soluble or readily disperse in water, so that when the polymer is placed in water or an aqueous environment (e.g. fluids in the gastrointestinal (GI) tract or simulated GI fluids), the solubility and/or bioavailability of suvorexant is increased over the solubility or bioavailability in the absence of the polymer.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behavior (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX 1 receptor and OX 2receptor as the two subtypes of orexin receptors.

Orexin receptors are found in the mammalian brain and the scientificliterature suggests that they may be involved in various pathologiessuch as depression; anxiety; addictions; obsessive compulsive disorder;affective neurosis; depressive neurosis; anxiety neurosis; dysthymicdisorder; behaviour disorder; mood disorder; sexual dysfunction;psychosexual dysfunction; sex disorder; schizophrenia; manic depression;delirium; dementia; severe mental retardation and dyskinesias such asHuntingtons disease and Tourette syndrome; eating disorders such asanorexia, bulimia, cachexia, and obesity; addictive feeding behaviors;binge/purge feeding behaviors; cardiovascular diseases; diabetes;appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer;Parkinsons disease; Cushings syndrome/disease; basophile adenoma;prolactinoma; hyperprolactinemia; hypophysis tumour/adenoma;hypothalamic diseases; inflammatory bowel disease; gastric diskinesia;gastric ulcers; Froehlichs syndrome; adrenohypophysis disease;hypophysis disease; adrenohypophysis hypofunction; adrenohypophysishyperfunction; hypothalamic hypogonadism; Kallmans syndrome (anosmia,hyposmia); functional or psychogenic amenorrhea; hypopituitarism;hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction;idiopathic hyperprolactinemia; hypothalamic disorders of growth hormonedeficiency; idiopathic growth deficiency; dwarfism; gigantism;acromegaly; disturbed biological and circadian rhythms; sleepdisturbances associated with diseases such as neurological disorders,neuropathic pain and restless leg syndrome; heart and lung diseases,acute and congestive heart failure; hypotension; hypertension; urinaryretention; osteoporosis; angina pectoris; myocardinal infarction;ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers;allergies; benign prostatic hypertrophy; chronic renal failure; renaldisease; impaired glucose tolerance; migraine; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; conditions associated with visceralpain such as irritable bowel syndrome, and angina; migraine; urinarybladder incontinence e.g. urge incontinence; tolerance to narcotics orwithdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy;insomnia; parasomnia; jet lag syndrome; and neurodegenerative disordersincluding nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders and otherdiseases related to general orexin system dysfunction.

The compound of the formula I:

5-chloro-2-(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl-1,3-benzoxazole(aka. “suvorexant”) is disclosed as an antagonist of orexin receptors inU.S. Pat. No. 7,951,797, US Patent Application Publication US2008/0132490, PCT Patent Publication WO 2008/069997, Cox et al., J. Med.Chem. 2010, 53, 5320-5332, Strotman et al., JACS, 2011, 133(21),8362-8371, Baxter et al., Org. Process Res. & Dev., 2011, 15(2) 367-375.This compound may be named as, e.g.,5-chloro-2-(5R)-5-methyl-4-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl-1,4-diazepan-1-yl-1,3-benzoxazole,(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl-1,4diazepan-1-yl-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanoneor (7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl5-methyl-2-(2H-1,2,3-triazol-2-yl)phenylmethanone.

SUMMARY OF THE INVENTION

The present invention is directed to a pharmaceutical compositioncomprising the compound suvorexant, or a pharmaceutically acceptablesalt thereof, a concentration-enhancing polymer, and optionally apharmaceutically acceptable surfactant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of a hot meltextrusion formulation of suvorexant.

FIG. 2 shows the modulated differential scanning calorimetry (mDSC)thermogram of a hot melt extrusion formulation of suvorexant.

FIG. 3 shows the Raman spectrogram of a hot melt extrudate ofsuvorexant.

FIG. 4 shows the Raman spectrogram of a tablet formulation thatcomprises a hot melt extrudate of suvorexant.

FIG. 5 shows the Raman spectrogram of a hot melt extrudate of suvorexantoverlayed with the Raman spectrogram of a tablet formulation thatcomprises a hot melt extrudate of suvorexant, and further overlayed withthe Raman spectrogram of individual excpients in such tablet formulationthat comprises a hot melt extrudate of suvorexant.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a pharmaceutical compositioncomprising:

(1) suvorexant, or a pharmaceutically acceptable salt thereof;

(2) a concentration-enhancing polymer, where the polymer increases thebioavailability of suvorexant, and is water soluble or readily dispersesin water; and

(3) optionally one or more surfactants.

The concentration-enhancing polymer is a polymer that forms an amorphousdispersion with suvorexant, that is insoluble or almost completelyinsoluble in water by (a) dissolving the suvorexant or (b) interactingwith the suvorexant in such a way that the suvorexant does not formcrystals or crystalline domains in the polymer. Aconcentration-enhancing polymer is water soluble or readily disperse inwater, so that when the polymer is placed in water or an aqueousenvironment (e.g. fluids in the gastrointestinal (GI) tract or simulatedGI fluids), the solubility and/or bioavailability of suvorexant isincreased over the solubility or bioavailability in the absence of thepolymer.

One class of polymers suitable for use with the present inventioncomprises neutral non-cellulosic polymers. Exemplary polymers include:vinyl polymers and copolymers having substituents that are hydroxy,alkyl, acyloxy, and cyclic amides. These include polyvinyl alcohols thathave at least a portion of their repeat units in the unhydrolyzed (vinylacetate) form (e.g. polyvinyl alcohol-polyvinyl acetate copolymers);polyvinyl pyrrolidinone; polyethylene polyvinyl alcohol copolymers; andpolyvinylpyrrolidinone-polyvinyl acetate copolymers. A class ofnon-cellulosic nonionic polymers comprises polyvinylpyrrolidinone andpolyvinylpyrrolidinone copolymers, such aspolyvinylpyrrolidinone-polyvinyl acetate copolymers, available asKollidon polymers and copolymers or Plasdone polymers and copolymers. Arepresentative copolymer is copovidone. These copolymers are often soldunder the Kollidon VA64 or Plasdone S630 trademarks. A representativecopolymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft copolymer. This copolymer is often sold under the Soluplustrademark.

Another class of polymers suitable for use with the present inventioncomprises ionizable non-cellulosic polymers. Exemplary polymers include:carboxylic acid functionalized vinyl polymers, such as the carboxylicacid functionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates. This copolymer is often sold under the EUDRAGITStrademark, by Rohm Tech Inc., of Malden, Mass.; amine-functionalizedpolyacrylates and polymethacrylates; proteins; and carboxylic acidfunctionalized starches such as starch glycolate.

Concentration enhancing polymers may also be non-cellulosic polymersthat are amphiphilic, which are copolymers of a relatively hydrophilicand a relatively hydrophobic monomer. Examples include the acrylate andmethacrylate copolymers (EUDRAGITS) mentioned previously. Anotherexample of amphiphilic polymers are block copolymers of ethylene oxide(or glycol) and propylene oxide (or glycol), where the poly(propyleneglycol) oligomer units are relatively hydrophobic and the poly(ethyleneglycol) units are relatively hydrophilic. These polymers are often soldunder the Poloxamer trademark.

A class of polymers comprises ionizable and neutral cellulosic polymerswith at least one ester- and/or ether-linked substituent in which thepolymer has a degree of substitution of at least 0.1 for eachsubstituent. In the nomenclature used herein, ether-linked substituentsare recited prior to “cellulose” as the moiety attached to the cellulosebackbone by an ether linkage; for example, “ethylbenzoic acid cellulose”has ethoxybenzoic acid substituents on the cellulose backbone.Analogously, ester-linked substituents are recited after “cellulose” asthe carboxylate; for example, “cellulose phthalate” has one carboxylicacid of each phthalate moiety ester-linked to the polymer, with theother carboxylic acid group of the phthalate group remaining as a freecarboxylic acid group.

It should also be noted that a polymer name such as cellulose acetatephthalate (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate groups attached via ester linkages to asignificant fraction of the cellulosic polymers hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from 0.1 to 2.9 as long as the other criteria of the polymer aremet. Degree of substitution refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate substituted, the phthalate degree ofsubstitution is 3.

Also included within each polymer family type are cellulosic polymersthat have additional substituents added in relatively small amounts thatdo not substantially alter the performance of the polymer.

Amphiphilic cellulosics may be prepared by substituting the cellulose atany or all of the 3 hydroxyl substituents present on each sacchariderepeat unit with at least one relatively hydrophobic substituent.Hydrophobic substituents may be essentially any substituent that, ifsubstituted at a high enough level or degree of substitution, can renderthe cellulosic polymer essentially aqueous insoluble. Hydrophilicregions of the polymer can be either those portions that are relativelyunsubstituted, since the unsubstituted hydroxyls are themselvesrelatively hydrophilic, or those regions that are substituted withhydrophilic substituents. Examples of hydrophobic substituents includeether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; orester-linked alkyl groups such as acetate, propionate, butyrate, etc.;and ether- and/or ester-linked aryl-groups such as phenyl, benzoate, orphenylate. Hydrophilic groups include ether- or ester-linkednonionizable groups such as the hydroxyalkyl substituents hydroxyethyl,hydroxypropyl, and the alkyl ether groups such as ethoxyethoxy ormethoxyethoxy. Hydrophilic substituents include those that are ether- orester-linked ionizable groups such as carboxylic acids, thiocarboxylicacids, substituted phenoxy groups, amines, phosphates or sulfonates.

One class of cellulosic polymers comprises neutral polymers, meaningthat the polymers are substantially non-ionizable in aqueous solution.Such polymers contain non-ionizable substituents, which may be eitherether-linked or ester-linked. Exemplary etherlinked non-ionizablesubstituents include: alkyl groups, such as methyl, ethyl, propyl,butyl, etc.; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.; and aryl groups such as phenyl. Exemplaryester-linked non-ionizable groups include: alkyl groups, such asacetate, propionate, butyrate, etc.; and aryl groups such as phenylate.However, when aryl groups are included, the polymer may need to includea sufficient amount of a hydrophilic substituent so that the polymer hasat least some water solubility at any physiologically relevant pH offrom 1 to 8.

Exemplary non-ionizable polymers that may be used as the polymerinclude: hydroxypropyl methyl cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethylcellulose.

An embodiment of neutral cellulosic polymers are those that areamphiphilic. Exemplary polymers include hydroxypropyl methyl celluloseand hydroxypropyl cellulose acetate, where cellulosic repeat units thathave relatively high numbers of methyl or acetate substituents relativeto the unsubstituted hydroxyl or hydroxypropyl substituents constitutehydrophobic regions relative to other repeat units on the polymer.

An embodiment of cellulosic polymers comprises polymers that are atleast partially ionizable at physiologically relevant pH and include atleast one ionizable substituent, which may be either ether-linked orester-linked. Exemplary ether-linked ionizable substituents include:carboxylic acids, such as acetic acid, propionic acid, benzoic acid,salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid orpropoxybenzoic acid, the various isomers of alkoxyphthalic acid such asethoxyphthalic acid and ethoxyisophthalic acid, the various isomers ofalkoxynicotinic acid, such as ethoxynicotinic acid, and the variousisomers of picolinic acid such as ethoxypicolinic acid, etc.;thiocarboxylic acids, such as 5 thioacetic acid; substituted phenoxygroups, such as hydroxyphenoxy, etc.; amines, such as aminoethoxy,diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such asphosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplaryester linked ionizable substituents include: carboxylic acids, such assuccinate, citrate, phthalate, terephthalate, isophthalate,trimellitate, and the various isomers of pyridinedicarboxylic acid,etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxygroups, such as aminosalicylic acid; amines, such as natural orsynthetic amino acids, such as alanine or phenylalanine; phosphates,such as acetyl phosphate; and sulfonates, such as acetyl sulfonate. Foraromatic-substituted polymers to also have the requisite aqueoussolubility, it is also desirable that sufficient hydrophilic groups suchas hydroxypropyl or carboxylic acid functional groups be attached to thepolymer to render the polymer water soluble at least at pH values whereany ionizable groups are ionized. In some cases, the aromatic group mayitself be ionizable, such as phthalate or trimellitate substituents.

Exemplary cellulosic polymers that are at least partially ionized atphysiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethylcellulose, carboxymethyl cellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, hydroxypropyl methyl cellulose acetate succinate phthalate,hydroxypropyl methyl cellulose succinate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

Exemplary cellulosic polymers that meet the definition of amphiphilic,having hydrophilic and hydrophobic regions include polymers such ascellulose acetate phthalate and cellulose acetate trimellitate where thecellulosic repeat units that have one or more acetate substituents arehydrophobic relative to those that have no acetate substituents or haveone or more ionized phthalate or trimellitate substituents.

A subset of cellulosic ionizable polymers are those that possess both acarboxylic acid functional aromatic substituent and an alkylatesubstituent and thus are amphiphilic. Exemplary polymers includecellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxylpropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

Another subset of cellulosic ionizable polymers are those that possess anon-aromatic carboxylate substituent. Exemplary polymers includehydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate,hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, and hydroxyethyl cellulose acetate succinate.

As listed above, a wide range of polymers may be used to form amorphousdispersions of suvorexant. In an embodiment of the present invention,the concentration-enhancing polymer comprises a cellulosic polymer thatis water soluble in their nonionized state and are also water soluble intheir ionized state. A particular subclass of such polymers are theso-called enteric polymers, which include, for example, certain gradesof hydroxypropyl methyl cellulose acetate phthalate and celluloseacetate trimellitate. Dispersions formed from such polymers generallyshow large enhancements of the maximum drug concentration in dissolutiontests relative to that for a crystalline drug control. In addition,non-enteric grades of such polymers and closely related cellulosicpolymers are also useful.

In an embodiment of the present invention, the concentration-enhancingpolymer comprises hydroxypropyl methyl cellulose acetate succinate(HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), celluloseacetate phthalate (CAP), cellulose acetate trimellitate (CAT), methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,cellulose acetate terephthalate and cellulose acetate isophthalate.

In an embodiment of the present invention, the concentration-enhancingpolymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulosephthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetatetrimellitate (CAT), methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, celluloseacetate isophthalate, polyvinylpyrrolidinone, vinyl pyrrolidinone/vinylacetate copolymers, and acrylate and methacrylate copolymers.

In an embodiment of the present invention, the concentration-enhancingpolymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS) ora vinyl pyrrolidinone/vinyl acetate copolymer.

In an embodiment of the present invention, the concentration-enhancingpolymer is a pH-insensitive polymer. The term pH-insensitive polymermeans a polymer that has no appreciable differences in solubilitybetween gastric pH (pH 1-4) and intestinal pH (pH 5-8). RepresentativepH-insensitive polymers include: vinyl pyrrolidinone/vinyl acetatecopolymer, polyvinyl pyrrolidinone/vinyl acetate copolymer,hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose,polyvinyl pyrrolidinone, methacrylate copolymer, polyethylene oxide,polyoxypropylene/polyoxyethylene copolymers (poloxamers), andpolyethylene glycol. In an embodiment of the present invention, theconcentration-enhancing polymer is vinyl pyrrolidinone/vinyl acetatecopolymer or polyvinyl pyrrolidinone/vinyl acetate copolymer.

In an embodiment of the present invention, the concentration-enhancingpolymer is a vinyl pyrrolidinone/vinyl acetate copolymer. In anembodiment of the present invention, the concentration-enhancing polymeris polyvinyl pyrrolidinone/vinyl acetate copolymer.

When specific polymers that are suitable for use in the compositions ofthe present invention are blended, the blends of such polymers may alsobe suitable. Thus the term polymer is intended to include blends ofpolymers in addition to a single species of polymer.

The pharmaceutical composition of the present invention may optionallycomprise one or more surfactants, which may be ionic or nonionicsurfactants. The surfactants can increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum concentration ofdissolved drug. The surfactants may also make the dispersion easier toprocess. Surfactants may also stabilize the amorphous dispersions byinhibiting crystallization or precipitation of the drug by interactingwith the dissolved drug by such mechanisms as complexation, formation ofinclusion complexes, formation of micelles, and adsorption to thesurface of the solid drug. Suitable surfactants include cationic,anionic, and nonionic surfactants. These include for example fatty acidsand alkyl sulfonates; cationic surfactants such as benzalkonium chloride(Hyamine 1622, available from Lonza, Inc., Fairlawn, N.J.); anionicsurfactants, such as dioctyl sodium sulfosuccinate (Docusate Sodium,available from Mallinckrodt Spec. Chem., St. Louis, Mo.) and sodiumlauryl sulfate (sodium dodecyl sulfate); sorbitan fatty acid esters(SPAN series of surfactants); Vitamin E TPGS; polyoxyethylene sorbitanfatty acid esters (Tween series of surfactants, available from ICIAmericas Inc., Wilmington, Del.); polyoxyethylene castor oils andhydrogenated castor oils such as Cremophor RH-40 and Cremopher EL;Liposorb P-20, available from Lipochem Inc., Patterson N.J.; CapmulPOE-0, available from Abitec Corp., Janesville, Wis.), and naturalsurfactants such as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides.

The pharmaceutical composition of the present invention may optionallycomprise other excipients, such as one or more disintegrants, diluentsor lubricants. Representative disintegrants may include croscarmellosesodium, sodium starch glycolate, crospovidone, and starch.Representative glidants may include silicon dioxide and talc.Representative lubricants may include magnesium stearate, stearic acid,and sodium stearyl fumarate. Representative diluents may includemicrocrystalline cellulose, lactose, and mannitol.

An embodiment of the present invention is directed to a pharmaceuticalcomposition that comprises a concentration-enhancing polymer and 4-40%of suvorexant, or a pharmaceutically acceptable salt thereof. Anembodiment of the present invention is directed to a pharmaceuticalcomposition that comprises a concentration-enhancing polymer and 6-20%of suvorexant, or a pharmaceutically acceptable salt thereof. Anembodiment of the present invention is directed to a pharmaceuticalcomposition that comprises a concentration-enhancing polymer and 8-15%of suvorexant, or a pharmaceutically acceptable salt thereof. In anembodiment of the present invention, formulations of copovidone withsuvorexant and an optional surfactant may comprise 4%-40% suvorexant and0-10% surfactant, with the balance of the formulation being copovidone.In an embodiment of the present invention, formulations of Kollidon VA64with suvorexant and an optional surfactant may comprise 4%-40%suvorexant and 0-10% surfactant, with the balance of the formulationbeing Kollidon VA64. In an embodiment of the present invention,formulations of Plasdone S630 with suvorexant and an optional surfactantmay comprise 4%-40% suvorexant and 0-10% surfactant, with the balance ofthe formulation being Plasdone S630. In an embodiment of the presentinvention, formulations of Soluplus with suvorexant and an optionalsurfactant may comprise 4%-40% suvorexant and 0-10% surfactant, with thebalance of the formulation being Soluplus. In an embodiment of thisinvention, formulations of HPMCAS with suvorexant and an optionalsurfactant may comprise 4%-40% suvorexant and 0-10% surfactant, with thebalance of the formulation being HPMCAS.

The pharmaceutical compositions of the present invention are prepared byprocesses that are suitable for causing a compound (the drug) to form adispersion (also referred to as an amorphous dispersion) in the polymersuch that the drug is generally amorphous or dissolved in the polymer ora component of the composition, such as a surfactant. The dispersionsare stable, and the drug does not form crystals or other insolubleparticles. Such methods include solution methods, such as spray drying,spray coating, freeze-drying, and evaporation of a co-solvent undervacuum or by heating a solution of polymer and drug. Such methods alsoinclude methods that blend the solid drug with the polymer in the moltenstate, such as hot melt extrusion, and methods of compounding the solidnon-molten polymer and drug under heat and pressure to form adispersion.

Another aspect of the present invention is directed to a process forpreparing a composition comprising suvorexant, or a pharmaceuticallyacceptable salt thereof molecularly dispersed in or dissolved in aconcentration-enhancing polymer. In some embodiments it is preferred toselect the polymer used in a composition of the invention from thoseconcentration-enhancing polymers providing the following properties: (i)suvorexant is soluble in the polymer; (ii) suvorexant forms a solutionor dispersion behaving as a eutectic which has a melting point below themelting point of suvorexant; (iii) when suvorexant is admixed with theselected polymer(s) and heated it apparently acts as a fluxing agent topromote melting the polymer and promote dissolution of suvorexant intothe polymer. In some embodiments the process for preparing a compositionof the invention comprises: (i) forming a admixture of suvorexant andthe selected polymer; (ii) forming a molten dispersion by heating theadmixture to a temperature above about 60° C. and below about 200° C.,optionally with stirring of the molten dispersion; (iii) cooling thedispersion provided in Step (ii) to form a solid; and (iv) optionallyforming a shaped mass from the dispersion either before orcontemporaneously with Cooling Step (iii).

Processes for making pharmaceutical compositions of suvorexant with aconcentration-enhancing polymer include (a) hot melt extrusion and (b)spray drying. In an embodiment of the present invention, polymers foruse in these processes are polyvinylpyrrolidinone,polyvinylpyrrolidinone-polyvinylacetate copolymers (for examplecopovidone), HPC, HPMCAS, HPMC, HPMCP, CAP, and CAT. In an embodiment ofthe present invention, polymers for use in hot melt extrusion arepolyvinylpyrrolidinone and polyvinylpyrrolidinone-polyvinylacetatecopolymers (copovidone such as Kollidon VA64 or Plasdone S630). In anembodiment of the present invention, the polymer for use in hot meltextrusion is copovidone. In an embodiment of the present invention, thepolymer for use in hot melt extrusion is Kollidon VA64. In an embodimentof the present invention, the polymer for use in hot melt extrusion isPlasdone S630. In an embodiment of the present invention, the polymerfor use in hot melt extrusion is Soluplus. In an embodiment of thepresent invention, polymers for spray drying include HPC, HPMCAS, HPMC,HPMCP, CAP, and CAT. In an embodiment of the present invention, thepolymer for spray drying is HPMCAS.

Both of these processes are well known in the art. In spray drying, thepolymer, active compound, and other optional ingredients, such assurfactants, are dissolved in a solvent and are then sprayed through anozzle as a fine spray into a chamber where the solvent is evaporatedquickly to make fine particles comprising polymer, drug, and optionalother ingredients. The solvent is any solvent in which all of thecomponents of the composition are soluble and which is readilyevaporated in a spray drier. The solvent should also be suitable for usein preparing pharmaceutical compositions. Exemplary solvents areacetone, methanol and ethanol. Methanol and acetone are preferred. Inhot melt extrusion, the polymer, drug, and optional surfactants aremixed together in a wet granulation process or other mixing process, andthen the mixture of polymer, drug and surfactant are fed into thechamber of an extruder, preferably a twin screw extruder to obtainbetter mixing, and are then thoroughly melted and mixed to make anamorphous dispersion. In an embodiment of the present invention,chemical or physical foaming of the amorphous dispersion may beemployed. Amorphous dispersion that has been subjected to foaming mayimprove milling performance and provide more rapid dissolution throughincreased surface area.

In accordance with the present invention, a melt can be prepared in anyconvenient apparatus in which an admixture of suvorexant and polymer canbe heated and optionally stirred. Solidification can be carried out bymerely cooling the melt by any means convenient and in any containerconvenient. Once a solid is obtained, the solid can be furthermechanically processed to provide a convenient form for incorporationinto a medicament, for example, tablets or capsules.

It will be appreciated that other methods of preparing a melt,solidifying it, and forming the solid into conveniently sized particlescan be utilized without departing from the scope of the invention. Forexample, conveniently, compositions of the invention may be preparedusing an extruder. When an extruder is employed to prepare compositionsof the invention, conveniently, the material may be introduced into theextruder either in a pre-flux state, that is, as a dry admixture, or ina fluxed state, that is in a melted, plastic, or semi-solid stateachieved after the application of sufficient heat to the admixture tocause the suvorexant to dissolve in the polymer, optionally when afluxed charge is prepared, blending may be employed during heating topromote uniformity of the fluxed material.

If the material is introduced to the extruder in a fluxed state,residence time in the extruder is selected to be just sufficient toinsure homogeneity of the composition and the temperature is preferablymaintained in the extruder at a level just sufficient to insure that thematerial maintains its plasticity so that it can be extruded into aconveniently shaped extrudate. If the material is introduced into anextruder in a pre-flux state, the extruder components, for example, thebarrels and any mixing chamber present in the equipment, will bemaintained at a temperature sufficient to promote fluxing of theadmixture. Temperatures selected for use in processing a compositionwill also take into account that blending which occurs within theextruder equipment, for example, in a mixing section of the barrels,will also contribute to localized fluxing of the admixture by impartingshear-stresses that induce heating in the mixture. Additionally it willbe appreciated that equipment temperatures and residence times will beselected to minimize the amount of time that the admixture placed intothe extruder spends under conditions of heating and/or shear stress soas to minimize the amount of suvorexant which is decomposed duringformation of the composition, as discussed above. In general, extrusionprocesses in which heating is applied to the material extruded aretermed hot-melt/extrusion processes. When compositions of the presentinvention are prepared using extruder equipment, the extrudate thusprovided can be in any convenient shape, for example, noodles,cylinders, bars, or the like. If desired, the extrudate can be furtherprocessed, for example by milling, to provide a particulate form of thecomposition.

In an alternate embodiment, the present invention is directed to anamorphous form of the compound suvorexant. In an alternate embodiment,the present invention is directed to an isolated amorphous form of thecompound suvorexant. In an embodiment of the present invention, thepharmaceutical composition of suvorexant and concentration-enhancingpolymer is prepared according to any known process which results in atleast a major portion of suvorexant is present in the amorphous staterelative to other morphological forms of suvorexant. These processesinclude mechanical processes, such as milling and extrusion; meltprocesses, such as high temperature fusion, hot melt extrusion, solventmodified fusion, and melt congealing processes; and solvent processes,including non-solvent precipitation processes, spray coating, andspray-drying. Although the dispersions of the present invention may bemade by any of these processes, in an embodiment of the inventionsuvorexant in the pharmaceutical composition is substantially amorphousand is substantially homogeneously distributed throughout the polymer.

In an alternate embodiment, the present invention is directed tosuvorexant in a form which contains at least about 40 wt. % of theamorphous form relative to other morphological forms of suvorexant. Inan alternate embodiment, the present invention is directed to suvorexantin a form which contains at least about 50 wt. % of the amorphous formrelative to other morphological forms of suvorexant. In an alternateembodiment, the present invention is directed to suvorexant in a formwhich contains at least about 60 wt. % of the amorphous form relative toother morphological forms of suvorexant. In an alternate embodiment, thepresent invention is directed to suvorexant in a form which contains atleast about 70 wt. % of the amorphous form relative to othermorphological forms of suvorexant. In an alternate embodiment, thepresent invention is directed to suvorexant in a form which contains atleast about 80 wt. % of the amorphous form relative to othermorphological forms of suvorexant. In an alternate embodiment, thepresent invention is directed to suvorexant in a form which contains atleast about 90 wt. % of the amorphous form relative to othermorphological forms of suvorexant. In an alternate embodiment, thepresent invention is directed to suvorexant in a form which contains atleast about 95 wt. % of the amorphous form relative to othermorphological forms of suvorexant. In an alternate embodiment, thepresent invention is directed to suvorexant in a form which contains atleast about 98 wt. % of the amorphous form relative to othermorphological forms of suvorexant. In an alternate embodiment, thepresent invention is directed to suvorexant in a form which contains atleast about 99 wt. % of the amorphous form relative to othermorphological forms of suvorexant. The relative amounts of crystallineand amorphous suvorexant can be determined by several analyticalmethods, including differential scanning calorimetry (DSC), x-ray powderdiffraction (XRPD) and Raman spectroscopy.

The amorphous form of the compound suvorexant was prepared by dissolvinga sample of suvorexant in acetone then removing the acetone. Inparticular, the amorphous form of the compound suvorexant was preparedby dissolving a sample of suvorexant in acetone, heating the solution to60° C. then removing the acetone on a rotary evaporator. The resultantsolid was dried overnight in a vacuum oven at 40° C. to remove anyremaining solvent. The thermogram and the diffractogram of the resultingmaterial indicated that it was amorphous.

An embodiment of the present invention is directed to a process for thepreparation of an amorphous form of the compound suvorexant whichcomprises dissolving a sample of suvorexant in acetone then removing theacetone.

The amorphous form of the compound suvorexant may have benefits relativeto other morphological forms of suvorexant such as greater solubilityand/or a faster dissolution rate than crystalline forms of the compound,which may improve bioavailability of the compound, may facilitate afaster onset of therapeutic action, may reduce variability oftherapeutic response among subjects, and may reduce any food effect.

X-ray powder diffraction studies are widely used to characterizemolecular structures, crystallinity, and polymorphism. The X-ray powderdiffraction patterns were generated on a Philips Analytical XPert PROX-ray Diffraction System with PW3040/60 console. A PW3373/00 ceramic CuLEF X-ray tube K-Alpha radiation was used as the source.

DSC data were acquired using TA Instruments DSC 2910 or equivalentinstrumentation. A sample with a weight between 2 and 6 mg was weighedinto a pan and the pan was crimped. This pan was placed in the sampleposition in the calorimeter cell. An empty pan was placed in thereference position. The calorimeter cell was closed and a flow ofnitrogen is passed through the cell. The heating program was set to heatthe sample at a heating rate of 10° C./min to a temperature ofapproximately 200° C. When the run was completed, the data were analyzedusing the DSC analysis program in the system software. The observedendotherms were integrated between baseline temperature points that areabove and below the temperature range over which the endotherm isobserved. The data reported are the onset temperature, peak temperatureand enthalpy.

Raman spectroscopy is widely used to determine the composition andmorphological character of samples of interest. FT-Raman (Fouriertransform Raman) spectra were collected over the range of 50-4000 cm-1with a Bruker IFS 66v/S system coupled with the FRA106/S Ramanattachment. The signal was averaged for 5-10 minutes at a resolution of4 cm-1 and a laser power of 300-500 mW. The samples were presented tothe laser using a spinning stage which that was rotated during themeasurement to provide a large sampling volume.

FIG. 1 shows an X-ray powder diffraction pattern of a hot melt extrusionformulation of suvorexant. The X-ray powder diffraction patternindicates that the amorphous form of suvorexant is present. The absenceof sharp reflections indicate the lack of crystallinity.

FIG. 2 shows the modulated differential scanning calorimetry (mDSC)thermogram of a hot melt extrusion formulation of suvorexant. As notedby the thermogram, in hot melt extrusion formulations the compoundsuvorexant is present as an amorphous form that is characterized by asingle glass transition temperature. This sample exhibited a singleglass transition temperature of approximately 99° C.

FIG. 3 shows the Raman spectrogram of a hot melt extrudate ofsuvorexant.

As noted by the spectrogram, a hot melt extrudate of suvorexant in theamorphous form is characterized by a Raman spectrogram peak at 1614cm-1. A hot melt extrudate of suvorexant in the amorphous form isalternatively characterized by a Raman spectrogram peak at 1590 cm-1. Ahot melt extrudate of suvorexant in the amorphous form is alternativelycharacterized by a Raman spectrogram peak at 1571 cm-1.

FIG. 4 shows the Raman spectrogram of a tablet formulation thatcomprises a hot melt extrudate of suvorexant. As noted by thespectrogram, a tablet formulation that comprises a hot melt extrudate ofsuvorexant in the amorphous form is characterized by a Raman spectrogrampeak at 1614 cm-1. A tablet formulation that comprises a hot meltextrudate of suvorexant in the amorphous form is alternativelycharacterized by a Raman spectrogram peak at 1590 cm-1. A tabletformulation that comprises a hot melt extrudate of suvorexant in theamorphous form is alternatively characterized by a Raman spectrogrampeak at 1571 cm-1. A tablet formulation that comprises a hot meltextrudate of suvorexant in the amorphous form is alternativelycharacterized by Raman spectrogram peaks at 1614 cm-1, 1590 cm-1 and1571 cm-1.

FIG. 5 shows the Raman spectrogram of a hot melt extrudate of suvorexantoverlayed with the Raman spectrogram of a tablet formulation thatcomprises a hot melt extrudate of suvorexant, and further overlayed withthe Raman spectrogram of individual excpients in such tablet formulationthat comprises a hot melt extrudate of suvorexant.

Suvorexant is disclosed as having activity in antagonizing the humanorexin-1 (OX1) receptor with a Ki of 0.55 nM and in antagonizing thehuman orexin-2 (OX2) receptor with a Ki of 0.35 nM. Relative to standardpharmaceutical formulations of suvorexant, the present invention mayhave benefits such as providing greater solubility of suvorexant and/ora faster dissolution rate than standard formulations of the compound,which may improve bioavailability of the compound, may facilitate afaster onset of therapeutic action, may reduce variability oftherapeutic response among subjects, and may reduce any food effect.

The compositions comprising the concentration-enhancing polymer increasethe concentration of suvorexant in an aqueous environment, such aswater, the gastrointestinal (GI) tract, or a simulated GI fluid preparedfor in vitro laboratory tests relative to a control compositioncomprising an equivalent amount of suvorexant without polymer. Once thecomposition is introduced into an aqueous environment, the compositioncomprising the concentration-enhancing polymer and suvorexant provides ahigher maximum aqueous concentration of suvorexant relative to a controlcomposition having the same concentration of suvorexant but without theconcentration-enhancing polymer. An inert filler may be used in place ofthe polymer in the control to keep the suvorexant at the sameconcentration as in the composition comprising the polymer. In anembodiment of the present invention, the polymer increases the maximumconcentration of suvorexant in an aqueous solution by at least 25%. Inan embodiment of the present invention, the polymer increases themaximum concentration of suvorexant in an aqueous solution by at least50%. In an embodiment of the present invention, the polymer increasesthe maximum concentration of suvorexant in an aqueous solution to atleast double relative to a control composition. In an embodiment of thepresent invention, the polymer increases the maximum concentration ofsuvorexant in an aqueous solution to at least 5-times greater that thanthat of a control composition. In an embodiment of the presentinvention, the polymer increases the maximum concentration of suvorexantin an aqueous solution by at least 10-fold. Such large enhancements inconcentration may be necessary in order for suvorexant to achieveeffective blood levels through oral dosing. Such aqueous solutions aregenerally supersaturated solutions with respect to suvorexant.

In in vivo pharmacokinetics measurements in which the concentration ofsuvorexant is measured as a function of time in blood or serum afteradministration of the formulation to a test animal, the compositions ofthe present invention exhibit an area under the concentration versustime curve (AUC) and a maximum concentration Cmax that is greater thanthat of a control composition comprising an equivalent quantity of thecompound without the concentration-enhancing polymer. In an embodimentof the present invention, the area under the concentration versus timecurve (AUC) is at least 25% greater than that of a control composition.In an embodiment of the present invention, the AUC is at least 50%greater than that of a control composition containing the same amount ofdrug but without the polymer. In an embodiment of the present invention,the area under the AUC is at least double than that of a controlcomposition containing the same amount of drug but without the polymer.In an embodiment of the present invention, the area under the AUC is atleast 5-times greater than that of a control composition containing thesame amount of drug but without the polymer. In an embodiment of thepresent invention, the area under the AUC is at least 10-fold greaterthan that of a control composition containing the same amount of drugbut without the polymer. In an embodiment of the present invention, thearea under the AUC is at least 15-fold greater than that of a controlcomposition containing the same amount of drug but without the polymer.In an embodiment of the present invention, the area under the AUC is atleast 20-fold greater than that of a control composition containing thesame amount of drug but without the polymer.

In an embodiment of the present invention, the Cmax is increased by atleast 25% relative to a control composition without theconcentration-enhancing polymer after it is administered to a testanimal or patient. In an embodiment of the present invention, the Cmaxis increased by at least 50% relative to a control composition withoutthe polymer after it is administered to a test animal or patient. In anembodiment of the present invention, the Cmax is increased by at leastdouble relative to a control composition without the polymer after it isadministered to a test animal or patient. In an embodiment of thepresent invention, the Cmax is also increased by at least 5-timesgreater that than that of a control composition without the polymerafter it is administered to a test animal or patient. In an embodimentof the present invention, the Cmax is also increased by at least 10times greater than the drug concentration of a control compositionwithout the polymer after it is administered to a test animal orpatient. In an embodiment of the present invention, the Cmax is alsoincreased by at least 20 times greater than the drug concentration of acontrol composition without the polymer after it is administered to atest animal or patient. In an embodiment of the present invention, theCmax is also increased by at least 30 times greater than the drugconcentration of a control composition without the polymer after it isadministered to a test animal or patient. In an embodiment of thepresent invention, the Cmax is also increased by at least 40 timesgreater than the drug concentration of a control composition without thepolymer after it is administered to a test animal or patient.

The pharmaceutical compositions of the present invention exhibitimproved in vivo bioavailability compared with formulations that do nothave the concentration-enhancing polymer. The compound suvorexant isabsorbed more rapidly after oral administration of these formulations.The AUC of the drug and the maximal concentration of the drug in theblood or serum are increased when the formulations are administered to apatient.

In in vivo pharmacokinetics measurements in which the concentration ofsuvorexant is measured as a function of time in blood or serum afteradministration of the formulation to a test animal or human patient uponco-administration with food (such as a high fat meal), the compositionsof the present invention that employ a concentration-enhancing polymerthat is a pH-insensitive polymer may exhibit a time to peakconcentration (Tmax) that is shorter than that of a compositioncomprising an equivalent quantity of the compound that employ aconcentration-enhancing polymer that is not a pH-insensitive polymer.Accordingly, the use of a concentration-enhancing polymer that is apH-insensitive polymer may help to reduce the food effect that otherwisedelays the Tmax when a formulation of suvorexant is administered withfood (such as a high fat meal).

Oral administration of a pharmaceutical composition of the presentinvention surprisingly reduces the food effect, that is, oraladministration of a formulation comprising a composition of theinvention provides substantially the same suvorexant exposure and lessvariability in bioavailability across a patient population regardless ofwhether the formulation is administered under Fed Conditions or FastedConditions. Moreover, when the results of oral administration of aformulation comprising a composition of the invention are compared tothose obtained after administration of an equivalent amount ofsuvorexant in the form of a conventional formulation, under either fedconditions or fasted conditions, the composition of the invention yieldsincreased bioavailability, with lower variability in bioavailabilityacross a population of subjects, and higher exposure levels (AUC) inhealthy volunteers to whom it is administered. Moreover, it is believedthat similar results are achieved in patients to whom formulationcomprising a composition of the invention is administered.

The term pharmaceutically acceptable salts refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids. Salts derived frominorganic bases include aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic salts, manganous, potassium,sodium, zinc, and the like. Particular embodiments include the ammonium,calcium, magnesium, potassium, and sodium salts. Salts in the solid formmay exist in more than one crystal structure, and may also be in theform of hydrates. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines, and basic ion exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. When the compound employedin the present invention is basic, salts may be prepared frompharmaceutically acceptable non-toxic acids, including inorganic andorganic acids. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.Particular embodiments include the citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will beunderstood that, as used herein, references to suvorexant are meant toalso include the pharmaceutically acceptable salts.

Exemplifying the invention is the use of the formulations disclosed inthe Examples and herein. Suvorexant or a pharmaceutically acceptablesalt thereof is useful in a method of antagonizing orexin receptoractivity in a patient such as a mammal in need of such inhibitioncomprising the administration of an effective amount of the compound.The present invention is directed to the use of the formulations ofsuvorexant or a pharmaceutically acceptable salt thereof as antagonistsof orexin receptor activity. In addition to primates, especially humans,it is possible that a variety of other mammals may be treated accordingto the method of the present invention.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term therapeutically effectiveamount means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms treatment and treatingrefer to all processes wherein there may be a slowing, interrupting,arresting, controlling, or stopping of the progression of theneurological and psychiatric disorders described herein, but does notnecessarily indicate a total elimination of all disorder symptoms, aswell as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms administration of and or administering a compoundshould be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the individual in need thereof

The term composition as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By pharmaceutically acceptable it is meant the carrier, diluentor excipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The scientific literature has implicated the orexin receptors in a widerange of biological functions. This has suggested a potential role forthese receptors in a variety of disease processes in humans or otherspecies. In accordance with the present invention, the formulations ofsuvorexant or a pharmaceutically acceptable salt thereof may haveutility in treating, preventing, ameliorating, controlling or reducingthe risk of neurological and psychiatric disorders associated withorexin receptors. In accordance with the present invention, theformulations of suvorexant or a pharmaceutically acceptable salt thereofmay provide methods for: preventing and treating sleep disorders andsleep disturbances; treating insomnia; enhancing the quality of sleep;augmenting sleep maintenance; increasing REM sleep; increasing stage 2sleep; decreasing fragmentation of sleep patterns; treating insomnia;enhancing cognition; increasing memory retention; treating orcontrolling obesity; treating or controlling depression; in a mammalianpatient in need thereof which comprises administering to the patient atherapeutically effective amount of suvorexant or a pharmaceuticallyacceptable salt thereof in a formulation of the present invention.

In accordance with the present invention, the formulations of suvorexantor a pharmaceutically acceptable salt thereof may also be useful in amethod for the prevention, treatment, control, amelioration, orreduction of risk of the diseases, disorders and conditions notedherein. The dosage of active ingredient in the compositions of thisinvention may be varied, however, it is necessary that the amount of theactive ingredient be such that a suitable dosage form is obtained. Theactive ingredient may be administered to patients (animals and human) inneed of such treatment in dosages that will provide optimalpharmaceutical efficacy. The selected dosage depends upon the desiredtherapeutic effect, on the route of administration, and on the durationof the treatment. The dose will vary from patient to patient dependingupon the nature and severity of disease, the patients weight, specialdiets then being followed by a patient, concurrent medication, and otherfactors which those skilled in the art will recognize. Generally, dosagelevels of between 0.0001 to 10 mg/kg. of body weight daily areadministered to the patient, e.g., humans and elderly humans, to obtaineffective antagonism of orexin receptors. The dosage range willgenerally be about 0.5 mg to 1.0 g. per patient per day which may beadministered in single or multiple doses. In one embodiment, the dosagerange will be about 0.5 mg to 500 mg per patient per day; in anotherembodiment about 0.5 mg to 200 mg per patient per day; and in yetanother embodiment about 5 mg to 50 mg per patient per day.Pharmaceutical compositions of the present invention may be provided ina solid dosage formulation such as comprising about 0.5 mg to 500 mgactive ingredient, or comprising about 1 mg to 250 mg active ingredient.The pharmaceutical composition may be provided in a solid dosageformulation comprising about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 40 mg, 50 mg, or 100 mg active ingredient. In specific embodiments,the pharmaceutical composition may be provided in a solid dosageformulation comprising about 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg activeingredient. For oral administration, the compositions may be provided inthe form of tablets containing 1.0 to 1000 milligrams of the activeingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250,300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compound may be administered on a regimen of 1 to 4times per day, such as once or twice per day. In an embodiment of thepresent invention, the compound may be administered in a regimen of onceper day in the evening, such as prior to initiating sleep.

Suvorexant or a pharmaceutically acceptable salt thereof that isemployed in the present invention may be used in combination with one ormore other drugs in the treatment, prevention, control, amelioration, orreduction of risk of diseases or conditions for which compounds of thepresent invention or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, suvorexant or a pharmaceutically acceptable salt thereof thatis employed in the present invention may be used in combination withother drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When suvorexant or a pharmaceutically acceptable salt thereofis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Such pharmaceutical compositionsare prepared without undue experimentation in accordance with themethods described herein and known in the art. Accordingly, thepharmaceutical compositions of the present invention include those thatalso contain one or more other active ingredients, in addition to acompound of the present invention.

The weight ratio of suvorexant or a pharmaceutically acceptable saltthereof to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The pharmaceutical compositions of this invention may conveniently bepresented in dosage unit form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing the active ingredient into association with the carrier whichconstitutes one or more accessory ingredients. In general, thepharmaceutical compositions are prepared by uniformly and intimatelybringing the active ingredient into association with a liquid carrier ora finely divided solid carrier or both, and then, if necessary, shapingthe product into the desired formulation. In the pharmaceuticalcomposition the active object compound is included in an amountsufficient to produce the desired effect upon the process or conditionof diseases. As used herein, the term composition is intended toencompass a product comprising the specified ingredients in thespecified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be prepared inaccordance with the methods described herein and other method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may further contain one or more agents selected from thegroup consisting of sweetening agents, flavoring agents, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets may contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. Compositionsfor oral use may also be presented as hard gelatin capsules wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil. Aqueoussuspensions contain the active materials in admixture with excipientssuitable for the manufacture of aqueous suspensions. Dispersible powdersand granules suitable for preparation of an aqueous suspension by theaddition of water provide the active ingredient in admixture with adispersing or wetting agent, suspending agent and one or morepreservatives.

Several methods for preparing the pharmaceutical formulations of thisinvention are illustrated in the following Examples. In some cases theorder of carrying out the foregoing examples may be varied to facilitatethe efficiency of the process or desired properties of the formulation.The following examples are provided so that the invention might be morefully understood. These examples are illustrative only and should not beconstrued as limiting the invention in any way.

EXAMPLES

Examples of preparations of pharmaceutical formulations are providedbelow. Bioavailability is determined in vivo by dosing trialformulations and/or other formulations of suvorexant to Beagle dogs at adose of 5 mg/kg of suvorexant and then measuring the amount ofsuvorexant in the serum or blood as a function of time. Comparisons aremade with other formulations containing the same amount and sameconcentration of suvorexant, such as a solid formulation withconventional excipients. Dissolution of the formulations in water orsimulated gastric fluid can be observed and measured to determine theconcentration and rate of dissolution of suvorexant in the fluid usingthe formulations of this invention or other formulations, includingformulations with conventional excipients as controls to determine theimprovements in dissolution using the formulations of this invention.

Example 1 Preparation of Spray Dry Formulations Formulation 1:

Spray dried formulations comprised: suvorexant (10-20% w/w); an optionalsurfactant, such as (1) 2-4% SDS (sodium dodecyl sulfate), (2) 2.5%Vitamin E TPGS, (3) 2% Tween 80, (4) 2% Span 80, or (5) 2% Cremophor EL,or a mixture of two or more of these surfactants; and the balance iseither HPMCAS-L, HPMCAS-M, or HPMCAS-H (purchased as AQOAT from ShinEtsu). The components were dissolved or suspended in a solvent system,such as acetone, methanol, and mixtures of organic solvents with water(0.5-18% w/v solids), and then spray dried as described below.

Solution Preparation:

Suvorexant, optional surfactant or surfactants, and polymer were mixedwith acetone, methanol, or mixtures of organic solvents with water asfollows, yielding a solution (which may be a structured suspension). Thedrug, surfactant, and polymer were dissolved in the solvent. The polymerwas slow to dissolve and was added to the solvent over an extendedperiod of time with vigorous stirring, such as by using an impeller ormagnetic stir bar and stir plate. The resulting solution/suspension wasstirred for at least an additional 60 min prior to spray drying.

Spray Drying Process 1:

Spray drying was carried out in a Niro SD Micro spray drier. Heated drynitrogen and formulation solution were fed concurrently into a two-fluidnozzle and then discharged as a spray into the drying chamber, alongwith additional heated gas, resulting in rapid evaporation to formparticles. The dried particles were carried by the processing gas into acyclone and then into a bag filter chamber for collection. Threeprocessing rates were controlled and monitored: 1) solution feed rate,2) processing nitrogen flow rate, and 3) atomizing nitrogen flow rate.The solution feed rate was controlled by an external peristaltic pump,and is 5-20 ml/min on a laboratory scale. The atomizing nitrogen rateand processing nitrogen rates were 2-3 kg/hr for atomizing nitrogen and20-30 kg/hr for processing nitrogen. The targeted processing gastemperature at the drying chamber outlet was slightly below the boilingpoint of the solvent system, although temperatures in the range of 30 to70° C. were demonstrated to be adequate, and the inlet chambertemperature (at the outlet of the nozzle) was adjusted to obtain thedesired outlet temperature. An inlet temperature set point of 80-90° C.was typical. Residual solvent levels in the product was typically low(1% w/w).

Spray Drying Process 2

The processing configuration was similar to Process 1, except that spraydrying was carried out in a Niro PSD-1 extended chamber spray drierequipped with a two-fluid nozzle with 1 mm orifice. The followingprocessing conditions were controlled or monitored: formulation solutionfeed rate (2-7.6 kg/hr), processing gas flow rate (35-38 mm H₂O),atomization ratio (ratio of atomization gas flow rate to feed rate)(0.9-2.8), atomization pressure (0.25-1.5 bar), outlet gas temperature(43-70° C.), and inlet gas temperature (61-134° C.)

Post Spray Drying Processing:

At the smaller processing scale, material collection occurred in twoareas, the cyclone and the bag filter chambers. Typical mean particlesizes resulting from the Spray Drying Process 1 ranged from 1 to 30 m,with individual particles measuring between 1 m and 100 m, as sampledfrom the cyclone collection area. The majority of particles in the bagfilter were 1 m or less, although the particles were highlyagglomerated. Under Spray Drying Process 2 conditions, particles wereharvested from the cyclone collection chamber only, and the typical meanparticle size may be much larger, typically ranging between 5 to 70 μm.

The spray dried particles were made into granules as follows. Theparticles were blended in a suitable blender (V or Bohle) withmicrocrystalline cellulose such as Avicel (a filler), lactose (afiller), croscarmellose sodium (a disintegrant), colloidal silicondioxide (a glidant), and magnesium stearate (a lubricant). The blendedpowders were then roller compacted into granules, subjected toextragranular lubrication, and filled into capsules.

A formulation prepared as described above that comprised of 10% (w/w)suvorexant, 40% HPMCAS-LF, 42.5% lactose monohydrate, 6% croscarmellosesodium, 0.5% colloidal silicon dioxide, and 1% magnesium stearate wastransferred to capsules, with each capsule containing 50 mg ofsuvorexant. The pharmacokinetic profile of this composition was testedin a panel of 3 fasted beagle dogs with a single dose of 1 mg/kg. Thepharmacokinetic measurements of suvorexant in the blood for a period of24 hours was as follows: AUC₀₋₂₄ is 52.319.1 M*hr; C_(max) is 6.952.23M; and T_(max) is 1.0 hr with a range of 1.0-2.0 hr.

For comparison, a formulation containing suvorexant without the polymeror spray drying process was made and tested, as follows. The non-polymerformulation contained 25% of suvorexant, 3% croscarmellose sodium, 1%magnesium stearate 35.5% microcrystalline cellulose, and 35.5% lactose,and was prepared by roller compaction and compressed into a tablet. Thepharmacokinetic profile of this composition was measured byadministering a single 5 mg/kg dose to a panel of 3 fasted beagle dogsand then measuring the amount of suvorexant in the blood of the dogs fora period of at least 24 hours. The pharmacokinetic data was as follows:AUC₀₋₂₄ is 3.041.40 M*hr, C_(max) is 0.340.10 M, and T_(max) is 2.0 hrwith a range of 1.0-2.0 hr. The pharmacokinetics are not as good for theconventional formulation as for the polymer formulations.

Example 2 Preparation of Hot Melt Extrusion Formulations

The following two formulations were made by hot melt extrusion. Amountsare expressed as weight %. KollidonVA64 is a copolymer ofpolyvinylpyrrolidinone and polyvinyl acetate having a co-monomer ratioof about 1.2:1. It is also known as copovidone. It has a glasstransition temperature (T_(g)) of about 110° C.

(1) suvorexant, 20%; Kollidon VA64, 80%.(2) suvorexant, 20%; HPMCAS-LG, 80%

Formulation 1

Formulation 1 was made by blending the two components, and then feedingthe mixture into a twin screw extruder. The mixture was made bycombining the KollidonVA64 polymer and suvorexant at room temperature ina Bohle bin blender equipped with a 2 liter bin.

The pre-extrusion blend was fed into a Thermo Prism 16 mm L/D 40:1 HotMelt Twin Screw Extruder. The barrel of the extruder had 10 temperaturezones numbered 1-10, with Zone 1 at the entry end of the barrel and Zone10 just before the die. Zone 1 was not heated and has no temperaturemeasurement. Zones 2-10 each have temperature control, and thetemperatures of each of these zones were measured. The temperature ofthe die was not controlled but can be measured. The feed was introducedinto Zone 2 through a feed throat. The screws were designed so thatmixing occurred across Zones 4 and 5. The mixing ended immediately pastthe vent port. The pre-extrusion mixture was fed into the feed port ofthe extruder at about 10 g/min from a K-Tron twin-screw gravimetricfeeder. The screw speed was 100 rpm. The profile of temperature setpoints in the extruder for Zones 2-10 was: Zones 2-5, 20° C.; Zones6-10, 130° C. The actual temperatures in these zones were: Zone 2,22-23° C.; Zone 4, 80° C.; Zones 6-10, 180° C. Zone 10 was initially setat 190° C. to avoid pressure during startup, and then the temperatureset point was lowered to 180° C. once the extrusion began. Thetemperature of the molten product exiting from the die was 200° C. Therewas no appreciable buildup of die pressure. The extrudate was clear, andit appeared homogeneous. The solid extruded polymer was then milledusing a Fitz Mill with a knife configuration, Impact forward, with a1722-0033 screen at 7500 rpm.

In an alternate procedure, a formulation was made by blending the twocomponents, and then feeding the mixture into a twin screw extruder. Themixture was made by combining the copovidone polymer and suvorexant atroom temperature in a bin blender. The pre-extrusion blend was fed intoa 40/1 L/D twin screw extruder. The extruder had 12 temperature zonesnumbered 1-12, with Zone 1 at the entry end of the barrel and Zone 10the end of the barrel sections with zone 11 being an adaptor to changethe flow regime to a single orifice and zone 12 being a die adaptor.Zone 1 was maintained at low temperatures by cooling water. Zones 2-12each have temperature control, and the temperatures of each of thesezones were measured. The feed was introduced into Zone 2 through a sidestuffer. The screws were designed so that a melt seal was formed at zone3 allowing moisture venting at zone 4. Mixing occurred across Zones 6and 7 allowing further moisture venting at zone 8. The pre-extrusionmixture was fed into the feed port of the extruder from a twin-screwgravimetric feeder. The screw speed was 300 rpm. The profile oftemperature set points in the extruder for Zones 2-12 was: Zone 2, 42°C.; Zone 3, 100° C.; zone 4, 130° C. Zones 5-12, 180° C. The temperatureof the molten product exiting from the die was 185° C. There was noappreciable build-up of die pressure. The extrudate was clear, and itappeared homogeneous. The extruded material was fed through counterrotating rolls chilled to 10-12° C. to bring the melt below its glasstransition temperature and form a brittle glass sheet, that was conveyedto a coarse mill, and broken up into small pieces. The extrudate wasthen further milled using an impact mill with a hammer configurationwith a 0.84 mm screen at mill tip speed of 40-45 m/s.

Formulation 2

Formulation 2 was made using the same procedure as was used forFormulation 1. The extrusion was carried out under the same generalconditions as the extrusion of Formulation 1. The only change was thatthe temperature of Zones 6-10 was set to 140° C. and Zone 10 wasinitially set at 150° C., before lowering back to 140° C. Thetemperature of the molten extrudate as it exited from the die was 140°C. The die pressure was low. The extrudate was milled using the samemethod as was used for Formulation 1.

Example 3 Preparation of Tablet Formulations by Hot Melt Extrusion

The formulation composition for making tablets containing 8% ofsuvorexant are shown in the following table. In accordance with thepresent invention, the compositions can be varied more broadly.

Component Composition (% w/w) Suvorexant  8% Copovidone 32% Lactosemonohydrate 16.5%   Microcrystalline cellulose 33% Croscarmellose sodium10% Magnesium stearate 0.5% 

Representative ranges of the amounts of the components that can be usedand their function are as follows: suvorexant (API), 0.5-40%; 5-30%copovidone (stabilizing polymer), 0.25-40%; microcrystalline cellulose(filler), 5-95%; lactose (filler), 5-95%; croscarmellose sodium(disintegrant), 1-10%; magnesium stearate (lubricant). Representativeranges of the amounts of suvorexant and copovidone are 1-40% and 5-90%,respectively.

In an embodiment of the present invention, substitutes may be used inplace of the polymers and excipients. For example, where a trade name orbrand name is used, the same materials having other brand or trade namesmay also be used: stabilizing polymerEudragits (acrylate-methacrylatecopolymers), PVP, HPC, HPMC, HPMCP, HPMCAS, CAS, CAP, and CAT;SurfactantsSDS, Cremophor (various grades), polysorbates (variousgrades), Solutol, Gelucires, Spans (various grades), PEGs;fillersdicalcium phosphate, silicified microcrystalline cellulose,starch, mannitol; disintegrantscrospovidone, sodium starch glycolate,calcium silicate, starch; optional colorantsred iron oxide, yellow ironoxide, black iron oxide, titanium dioxide, FD&C Blue 2; and optionalcoatingOpadry I, Opadry II, Opadry II HP.

Unit Strength = 10 mg Component mg/tablet Suvorexant 10Polyvinylpyrolidone/Vinyl Acetate Copolymer (Kollidon 40 VA64) Lactosemonohydrate (316 Fast-Flo) 20.625 Microcrystalline cellulose (AvicelPH102) 41.25 Croscarmellose sodium 12.5 Magnesium stearate 0.625 (CoreTablet Weight 125 mg)

Unit Strength = 30 mg Component mg/tablet Suvorexant 30Polyvinylpyrolidone/Vinyl Acetate Copolymer (Kollidon 120 VA64) Lactosemonohydrate (316 Fast-Flo) 61.875 Microcrystalline cellulose (AvicelPH102) 123.75 Croscarmellose sodium 37.5 Magnesium stearate 1.875 (CoreTablet Weight 375 mg)

The formulations in the table above were made by hot melt extrusion bythe following procedure. Suvorexant was fed using a Ktron K20 twin screwpowder feeder at extruder barrel zone 1 through the top feed port of thebarrel section (2 kg/hr). Polymer (Kollidon VA64) was fed using a KtronK20 twin screw powder feeder at extruder barrel zone 2 through a twinscrew Leistritz side stuffer with top vent port in the barrel section (8Kg/hr).

A vent (or two vents) were located at barrel zones 7, 8, and/or 9. Thesewere ambiently vented to remove water vapor. The remaining barrelsections were closed. All feeders are placed on load cells tocontinuously monitor changes in weight. The barrel temperature was atroom temperature at zone 1, and the temperatures were at about 130° C.at Zone 3 or 4. Zones 5-10 were heated to about 180° C.

A four hole strand die was used to extrude material onto a chilled rollunit made by ThermoElectron. The chilled roll unit used cool water toproduce a brittle sheet of extrudate that was subsequently chopped upinto particles by a kibbler (basically a rotor with perpendicular pegsthat wacks at the brittle sheet that is conveyed to the rotor).

The particles from the kibbler above were milled using a Fitz mill priorto downstream processing/tabletting. The milled extrudate was thenblended in a suitable blender (V or Tote) with microcrystallinecellulose (e.g. Avicel) (a filler), lactose (a filler), andcroscarmellose sodium (a disintegrant). The blend was then lubricatedwith magnesium stearate. The lubricated blend is compressed intotablets. The compressed tablets may optionally be coated.

The pharmacokinetic profile of this composition of suvorexant was testedby administering a single dose of the formulation at a dose of 5 mg/kgto panels of 3 fasted beagle dogs and measuring the concentration ofsuvorexant in the blood for a period of at least 24 hours. Thepharmacokinetic measurements of suvorexant were as follows: AUC0-24(M-hr) 2.82±0.493; Cmax (M) 0.5870.182; Tmax (hr) 1.0 (0.5-2.0).

The pharmacokinetic profile of this composition of suvorexant was alsotested by administering a single dose of the formulation to healthyhuman men. In this study, this composition of suvorexant helped toreduce the food effect when a formulation of suvorexant is administeredwith food (such as a high fat meal). In the first treatment period ofthis clinical study, a single, oral dose of this composition ofsuvorexant (40 mg) was administered to 7 subjects in a fasted state(following an 8-hour fast), and a single, oral dose of this compositionof suvorexant (40 mg) was administered to 7 different subjects followinga standard high-fat breakfast. In the second period of this clinicalstudy, the 7 subjects in each treatment groups were crossed over andreceived the other treatment.

As shown in the following table, AUC_(0-∞) and C_(max) for thiscomposition of suvorexant remained unchanged after administration with ahigh fat breakfast compared to administration in a fasted state. Thefed/fasted GMR and 90% confidence intervals for AUC_(0-inf) were 0.98(0.90, 1.07). The fed/fasted GMR and 90% confidence intervals forC_(max) were 1.09 (0.90, 1.33). Median T_(max) was 3.0 hours after ahigh fat breakfast and 2.0 hours in a fasted state. Mean apparentterminal t_(1/2) when administered after a high fat breakfast waslargely unchanged compared to administration in a fasted state, witht_(1/2) values of 11.8 and 10.9 hours respectively.

(Suvorexant Fed/ Pharmacokinetic Suvorexant Fasted Suvorexant FedSuvorexant Fasted) Parameter N GM 95% CI N GM 95% CI GMR 90% CIAUC_(0-∞) (μM · hr) 12 13.2 (10.60, 16.42) 12 13.0 (10.43, 16.16) 0.98(0.90, 1.07) C_(max) (μM) 13 1.0 (0.79, 1.22) 13 1.1 (0.86, 1.34) 1.09(0.90, 1.33) T_(max) (hr) 13 2.0 1.0, 4.0 13 3.0 1.0, 6.0 1.5 (1.0, 3.0)Apparent 12 10.9 3.4 12 11.8 3.8 — — Terminal t_(1/2) (hr) (GM:Geometric Mean, GMR: Geometric Mean ratio, CI: Confidence interval)

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A pharmaceutical composition comprising: (1)suvorexant, or a pharmaceutically acceptable salt thereof; (2) aconcentration-enhancing polymer, where the polymer increases thebioavailability of suvorexant, and is water soluble or readily dispersesin water.
 2. The pharmaceutical composition of claim 1, wherein theconcentration-enhancing polymer is selected from the group consisting ofionizable cellulosic polymers, nonionizable cellulosic polymers, andvinyl polymers and copolymers having substituents selected from thegroup consisting of hydroxy, alkyl, acyloxy, and cyclic amide.
 3. Thepharmaceutical composition of claim 2, wherein theconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropylmethyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP),cellulose acetate trimellitate (CAT), methyl cellulose acetatephthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetateterephthalate, cellulose acetate isophthalate, polyvinylpyrrolidinone,and polyvinylpyrrolidinone-polyvinylacetate copolymers.
 4. Thepharmaceutical composition of claim 3, wherein theconcentration-enhancing polymer is selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS), andhydroxypropyl methyl cellulose phthalate (HPMCP).
 5. The pharmaceuticalcomposition of claim 4, wherein the concentration-enhancing polymer ishydroxypropyl methyl cellulose acetate succinate (HPMCAS).
 6. Thepharmaceutical composition of claim 2, wherein theconcentration-enhancing polymer is selected from the group consisting ofvinyl polymers and copolymers having substituents selected from thegroup consisting of hydroxy, alkyl, acyloxy, and cyclic amide.
 7. Thepharmaceutical composition of claim 6, wherein theconcentration-enhancing polymer is selected from the group consisting ofpolyvinylpyrrolidinone and polyvinylpyrrolidinone-polyvinylacetatecopolymers.
 8. The pharmaceutical composition of claim 7, wherein theconcentration-enhancing polymer is apolyvinylpyrrolidinone-polyvinylacetate copolymer.
 9. The pharmaceuticalcomposition of claim 6, wherein the concentration-enhancing polymer is acopovidone copolymer.
 10. The pharmaceutical composition of claim 2,wherein the composition optionally comprises one or more surfactantsselected from the group consisting of anionic surfactants and nonionicsurfactants.
 11. The pharmaceutical composition of claim 10, wherein thecomposition optionally comprises one or more surfactants selected fromsodium dodecyl sulfate and one or more nonionic surfactants selectedfrom (a) sorbitan fatty acid esters, (b) polyoxyethylene sorbitan fattyacid esters, (c) polyoxyethylene castor oils, (d) polyoxyethylenehydrogenated castor oils, and (e) vitamin E TPGS; and mixtures thereof.12. The pharmaceutical composition of claim 1, wherein the aqueousconcentration of suvorexant is increased when the composition is placedinto an aqueous environment when compared with a control compositioncomprising an equivalent amount of suvorexant without polymer.
 13. Thepharmaceutical composition of claim 12, wherein the aqueousconcentration of suvorexant is increased by at least 25% when thecomposition is placed into an aqueous environment when compared with acontrol composition comprising an equivalent amount of the suvorexantwithout polymer.
 14. The pharmaceutical composition of claim 2, whereinthe composition is made by a process selected from: (1) spray drying ofa solution comprising suvorexant or a pharmaceutically acceptable saltthereof, the concentration-enhancing polymer, the optional one or moresurfactants, and one or more solvents; and (2) hot melt extrusion of amixture comprising suvorexant or a pharmaceutically acceptable saltthereof, the concentration-enhancing polymer, and the optional one ormore surfactants.
 15. The pharmaceutical composition of claim 14,wherein the composition is made by the spray drying of a solutioncomprising suvorexant or a pharmaceutically acceptable salt thereof, theconcentration-enhancing polymer, the optional one or more surfactants,and one or more solvents.
 16. The pharmaceutical composition of claim14, wherein the composition is made by hot melt extrusion of a mixturecomprising suvorexant or a pharmaceutically acceptable salt thereof, theconcentration-enhancing polymer, and optionally one or more surfactants.